Abstract

Objective Relatives of type 1 diabetic patients are at enhanced risk of developing diabetes. We investigated the mode of onset of hyperglycemia and how insulin sensitivity and ß-cell function contribute to the progression to the disease.

Research design and methods In 328 islet-cell-autoantibody-positive, non-diabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (age=11 [8] years (median [interquartile range]), sequential OGTTs (2,143 in total) were performed at baseline, every six months, and 2.7 [2.7] years later, when 115 subjects became diabetic. ß-cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses.

Results In progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of non-progressors, whereas ß-cell glucose sensitivity was impaired (48 [36] vs 87 [67] pmol^.min^−1.m^−2.mM⁻¹, p<0.0001), and predicted incident diabetes (p<0.0001) independently of sex, age, BMI, and clinical risk. In progressors, 2-hour glucose levels changed little until 0.78 years before diagnosis, when they started to rise rapidly (∼13 mmol^.l^−1.year⁻¹); glucose sensitivity began to decline significantly (p<0.0001) earlier (1.45 years before diagnosis) than the plasma glucose surge. During this anticipation phase, both insulin secretion and insulin sensitivity were essentially stable.

Conclusions In high-risk relatives, ß-cell glucose sensitivity is impaired and is a strong predictor of diabetes progression. The time trajectories of plasma glucose are frequently biphasic, a slow linear increase being followed by a rapid surge, and are anticipated by a further deterioration of ß-cell glucose sensitivity.